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Kidney Week

Abstract: PO0731

Cell Sex and Sex Hormones Regulate Kidney Metabolism of Glucose and Glutamine: Implications for Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Clotet Freixas, Sergi, University Health Network, Toronto, Ontario, Canada
  • Zaslaver, Olga, The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada
  • Pastrello, Chiara, University Health Network, Toronto, Ontario, Canada
  • Kotlyar, Max, University Health Network, Toronto, Ontario, Canada
  • McEvoy, Caitriona M., University Health Network, Toronto, Ontario, Canada
  • Farkona, Sofia, University Health Network, Toronto, Ontario, Canada
  • Saha, Aninda Dibya, University Health Network, Toronto, Ontario, Canada
  • Boshart, Alexander, University Health Network, Toronto, Ontario, Canada
  • Dart, Allison, University of Manitoba Department of Pediatrics and Child Health, Winnipeg, Manitoba, Canada
  • Wicklow, Brandy A., University of Manitoba Department of Pediatrics and Child Health, Winnipeg, Manitoba, Canada
  • Blydt-Hansen, Tom D., The University of British Columbia Department of Pediatrics, Winnipeg, Manitoba, Canada
  • Scholey, James W., University Health Network, Toronto, Ontario, Canada
  • Rost, Hannes L., The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada
  • Konvalinka, Ana, University Health Network, Toronto, Ontario, Canada
Background

Diabetic kidney disease (DKD) is the major cause of end-stage kidney disease. Male sex is a risk factor for DKD, but the reasons for this predilection are unclear. We demonstrated that androgens accentuate DKD in vivo, and increase enzymes involved in glucose and glutamine metabolism, in male proximal tubular epithelial cells (PTECs). We aimed to determine the effect of cell sex and sex hormones on kidney metabolism.

Methods

Male and female PTECs were stimulated with control, dihydrotestosterone (DHT), or estradiol. Sex differences in key metabolites were validated in diabetic mice, and in type 2 diabetic patients and their age- and weight-matched healthy controls (n=180, iCARE cohort).

Results

Male PTECs showed significantly higher glycolysis, oxygen consumption (OCR), glucose consumption, oxidative stress, and apoptosis, compared to female PTECs, especially in the presence of DHT. Higher OCR in male PTECs was further enhanced in the presence of glucose and glutamine, but not observed in the presence of pyruvate. Under high glucose, male PTECs showed a decline in OCR and ATP levels over time, and increased lactate production. Male PTECs had significantly higher intracellular levels of TCA cycle metabolites (glutamate, citrate, malate, aspartate) and glutathione metabolites. In turn, female cells had higher levels of pyruvate. In vivo, male sex was linked to increased circulating levels of glucose, lactate, and glutamate in healthy and diabetic mice. Male sex was also independently associated with increased serum levels of glutamate, succinate, fumarate, and 9 metabolites of the glutathione cycle, in healthy and diabetic individuals.

Conclusion

This is the first study to demonstrate that the kidney metabolism of glucose and glutamine is modulated by cell sex and sex hormones. Male sex was linked to increased oxidative stress, cell injury, glucose- and glutamine-related enzymes, lactate secretion, and levels of TCA cycle and glutathione metabolites. Our key findings were validated in the blood metabolome of healthy and diabetic humans. Our work has uncovered physiological sex differences that are important for DKD and may lead to new therapeutic paradigms based on patient sex.